Side Effects of Androgen Supplementation.

By far the most important possible side effect of androgen supplementation in elderly males is the exacerbation of prostatic disease.

T supplementation in elderly men induces only a minimal increase of the volume of the prostate with, eventually, a modest increase in levels of prostate specific antigen (PSA) (1,2,151). Hypogonadal men, treated for many years with T, developed a prostatic volume comparable to that of normal men of similar age (152). Hence, it appears that nonobstructive benign prostatic hyperplasia is not a contraindication for androgen substitution. However, obstructive benign prostatic hyperplasia constitutes a clear contraindication. Because almost all clinical prostatic carcinomas are androgen sensitive, the presence of this prostatic carcinoma is an absolute contraindication for androgen supplementation.

Recently, Hoffman et al. (153) reported the surprising finding that the levels of FT were inversely correlated with the incidence of prostatic carcinoma, and that low FT levels predicted a more aggressive neoplasm, whereas Kleinman and McKinlay (154), in the Massachusetts Male Aging Study, calculated that the hormone variables (T, FT, DHT, E2, androstenedione) would only account for 11% of our current knowledge about prostate cancer risk vs. 30% for nutrition and 40% for immutable factors (age, height, and family history). In this connection it is interesting to mention that Hardy et al. (155) observed an inverse correlation between the length of the AR CAG repeats and the risk of early onset of prostatic cancer.

Whereas in most studies T levels in prostatic CA patients and in normal controls were similar (156), Gann et al. (157) in a prospective study involving 222 subjects who, within 10 years of blood sampling, developed a prostatic carcinoma, matched with 390 controls of similar age observed when hormones and SHBG levels were simultaneously adjusted, an increased cancer risk for patients with high T levels.

A difficult problem constitutes the subclinical prostatic carcinoma, which is very frequent in elderly men (>50% of men over 70 yr old) and which is undetectable by clinical examination or laboratory techniques (PSA; transrectal ultrasonography) but only detectable by prostatic biopsy. Only a small percentage of these subclinical carcinomas will develop to a clinical carcinoma, but it is unknown whether T supplementation might stimulate its growth. There is no evidence that initiation of prostatic carcinoma is influenced by androgens. Whereas there is no geographical variation in the incidence of subclinical carcinoma (158), which is as frequent in the Far East as in Western countries, clinical carcinoma is very rare in the Far East, although (F)T levels are similar or only marginally lower in elderly Japanese men (159,160). This suggests that physiological T levels would not stimulate a subclinical carcinoma. Nevertheless, the androgen sensitivity of all clinical carcinomas pleads for prudence as the promotion of subclinical lesions to clinical carcinomas cannot be excluded (161).

The stimulatory effect of T on erythropoiesis is well documented. Whereas a moderate increase in hematocrit in elderly males is possibly beneficial, some studies reported an increase of the hematocrit over 51% (polycythemia) occurring in up to 25% of elderly patients (108, 120), requiring temporary withholding of the treatment and even phlebotomy. Available data suggest that the frequency of this side effect is related to supraphysiological levels (162). As transdermal patches yield T levels within the normal range, this may explain the reported lower frequency of polycythemia with this form of treatment, but more experience is required before to express a definitive opinion.

Whereas sleep apnea has been reported by Matsumoto et al. (163), none of the reports on T supplementation in elderly males mentioned the development of sleep apnea, which itself is often associated with lower T levels (164). Nevertheless, it is safe to consider obstructive pulmonary disease in overweight persons or heavy smokers as a relative contraindication.

As already discussed, T supplementation in physiological doses does not seem to induce an atherogenic lipid profile, but, as mentioned, T has also nonlipid mediated effects on the cardiovascular system. Water and sodium retention generally do not cause a problem, except in patients with heart decompensation, hypertension, or renal insufficiency. Hepatotoxicity is rare, even after the long-term use of relatively high oral doses of T-undecanoate in oleic acid (TU) (165), but is relatively frequent when synthetic 17 alkylated anabolic-androgenic steroids are used.

Gynecomastia is a benign complication of androgen supplementation, perhaps more frequent in elderly obese men than in young hypogonadal men. It is the consequence of the aromatization of T into estradiol in peripheral fat and muscle tissue.

Finally, T in supraphysiologcal doses suppresses spermatogenesis, but this should not be of major concern to elderly men.

Contraindications of Androgen Supplementation.

The presence of a clinical prostatic carcinoma is an absolute contraindication for HRT and should be carefully excluded by PSA, rectal examination and, eventually, biopsy before starting any therapy.

Benign nonobstructive prostatic hyperplasia is not a contraindication, but obstructive BPH is.

Polycythemia also constitutes a contraindication and the hematocrit should be controlled regularly during HRT.

A rare, absolute contraindication is mammary carcinoma in the male as well as a prolactinoma, as their growth may be stimulated by HRT.

Dyslipidemia is a relative contraindication requiring careful monitoring of the lipidmia during treatment.

As mentioned, COPD in overweight or heavy smoking patients often subject to sleep apnea constitutes a relative contraindication.

Modalities of Androgen Supplementation.

The major goal of T therapy is to replace T levels as close as possible to physiologic concentrations (166).

COMMENTARY 2385

T esters Because orally administered T is almost completely inactivated by its first pass through the liver, the only orally active form is TU that, due its lipophilic side chain, is partly taken up by the lymph and partly escapes hepatic inactivation.

The maximal plasma concentration of T is generally observed within 2-3 h, but after 6-8 h levels have returned to pretreatment levels. Hence, TU should be administered 2-3 times daily, preferably with a meal, in a dosage of 2-3 X 40 mg, which generally provides adequate androgen replacement, yielding T levels within the (low) normal range, whereas DHT levels are moderately increased (2-4 nmol/L) (167). However, the absorption is rather variable and the dose required should be determined on the basis of plasma levels and clinical effects.

Other orally active synthetic androgen/ anabolic steroids are either only weakly active (Mesterolon, Fluoxymesterone or hepatotoxic) due to the presence of an alkyl group in position 17. The most frequently used pharmaceutical form is the intramuscular administration of the hydrophobic long chain in oily depot, enanthate and the cypionate at a dose of 200-250 mg/2 weeks. However, this yields transient supraphysiological levels the first 2-3 days after injection, followed by a steady decline to subphysiological levels just before the next injection (168). These fluctuations in T levels are recognized by some of the patients as unpleasant and accompanied by changes in energy, libido, and mood, whereas the transient supraphysiological levels might increase the frequency of side effects (162).

Preliminary studies with im injection of 1000 mg TU indicate that this treatment might yield physiological T levels during 6-8 weeks (169). Longer acting T esters (4-6 months), such as the buciclate, are not suited for substitution in elderly males as, in the case of serious side effects, a rapid withdrawal of T should be possible.

Subcutaneous T pellets (6 X 100 mg every 4-6 months) provide stable physiological T levels; they are not widely used and not indicated in elderly men. In about 5% of the cases the pellets are extruded, and in a similar percentage a local infection may occur (170-172).

Transdermal scrotal or permeation-enhanced nonscrotal patches, delivering 4-6 mg T per day, provide, after nightly application, physiological T levels both in young and elderly hypogonadal men (116,162). Peak levels are obtained 2-4 h after application, decreasing afterward to two thirds of peak levels after 22-24 h, mimicking the normal circadian variation of T levels in young adults. The scrotal patches yield supranormal DHT levels (4-5 nmol/L), whereas the nonscrotal patches often cause local irritation. With a second generation torso patch (Testoderm torso patch) this, irritation would be seen less frequently. Besides providing physiological levels in young and elderly hypogonadal men (116), the patches have the advantage that the therapy can be immediately stopped when necessary (162, 173-175). Whether the increased DHT levels have deleterious effects is unknown.

A DHT gel is available (25-50 mg DHT/g) (176) at a dose of 125-250 mg/day, which yields plasma DHT levels comparable to physiological T levels; more recently it has been shown that in healthy elderly males, a lower dose of 32-64 mg/day yields comparable levels (177). DHT cannot be aromatized and, whereas it will not induce gynecomastia, it is probably inactive at the bone level. Wang et al. (177, 178) consider that the decrease in E2 levels by DHT gel treatment may be favorable at the level of the prostate, where estrogens stimulate the proliferation of the stroma. Recently a 1% hydro-alcoholic T gel has become available in some countries (98,179,180). When administered to young or elderly hypogonadal men, 12-68 yr of age, about 9-14% of the T applied was bioavailable and with a daily application of 100 mg/day contained in 10 g gel, the plasma T levels are in the upper normal quartile; DHT levels are only slightly increased. The surface area of inunction has only a slight influence on the T levels achieved. The gels permits an easy adaptation of the dose to the individual needs.

Other T formulations, such as bio-degradable T microspheres (181) or cyclodextrin complexed sublingual formulations (182, 183) are under experimentation.

Monitoring Androgen Supplementation.

During treatment, the eventual development of side effects should be carefully monitored by 6 monthly rectal examinations of the prostate, PS A, and hematocrit and plasma lipid determinations. Any increase of PSA by more than 0.75 ng/ml in two consecutive controls or a PSA level abnormal for age (>4 ng/ml) (184) requires further examination and eventually biopsy, whereas any increase of the hematocrit above 51% requires reduction of the dose or temporarily arrest of the treatment.

Further Developments

A major problem in the evaluation of the need of androgen supplementation is the absence of clinically useful biological parameters of androgen action, which would enable more exact evaluation of the androgen requirements of elderly men. Such parameters are urgently needed to identify objectively elderly men in need of androgen supplementation.

The biological effects of T are mediated by T itself (in muscle for example), by its 5a reduced metabolite, dihydrotestosterone, formed locally in target tissues (skin, external genitalia, and prostate) and by estradiol (bone and central nervous system). Local formation of DHT will stimulate prostatic growth and eventually prostatic carcinoma. Hence more organ selective androgens, specific AR modulators (SARMS) (185), with a desired profile of activity, stimulating only the desired organs (for example bone) without affecting other organs, would be a useful addition to our therapeutic arsenal.

17a methyl-19-nortestosterone, which does not undergo 5a reduction but does undergo aromatization and appears to be 10 times as active as T at the feed back, but only twice at the prostate level, is the first of such SARMS (186, 187) to provide adequate replacement in hypogonadal men (188). The existence of 2 forms of AR (AR-A and AR-B) (189) with different tissue distribution might contribute to the development of other SARMS.

Finally, we urgently need more carefully designed, well controlled, long-term, large-scale studies of HRT in healthy elderly men with subnormal T levels. These should permit an objective balance between the benefits and risks of HRT and, eventually, permit a wider application of HRT in elderly men.

VERMEULEN 2386 JCE & M . 2001
Vol. 86 • No. 6

General Conclusions

Aging is unavoidable and physiologic, but the large interindividual disparity in the pace of development and progression of signs and symptoms of aging, suggests that the development of this symptomatology can be delayed and that a high quality of life can be maintained until a very advanced age, in other words that it is possible to add life to years.

Being aware of these possibilities, more and more elderly men (and women) will seek medical help to achieve these goals.

Many signs and symptoms of aging in males are reminiscent of the symptoms of young hypogonadal men. These symptoms are often significantly (albeit often weakly) correlated with T levels. Therefore, although these symptoms have a complex origin it may be reasonably assumed that the age-associated decrease in T levels is in part responsible for these symptoms.

As shown in almost all studies, androgen supplementation in elderly men with subnormal T levels, has favorable, albeit often modest, effects on most of the symptoms, such as muscle mass and strength, fat mass, BMD, mood and general well-being. Therefore, it seems logical to consider that in elderly men with subnormal T levels and clinical symptoms suggestive of androgen deficiency, hormone replacement therapy in combination with physical activity (resistance training) and adequate nutrition will result in an optimal increase in muscle strength, BMD, and general sense of well-being. However, data on clinical effects of androgen substitution, such as cardiovascular morbidity and mortality, falls and bone fracture rates are so far not available.

The major contraindication for androgen supplementation is the presence of a prostatic carcinoma. The promising results obtained so far may nevertheless raise the hope that, when more research will have been performed, it will be possible to define accurately the indications for androgen supplementation and identify the elderly to profit most of the treatment.

Hormonal therapy then, together with adequate physical activity and a healthy life style might delay the aging process, prevent disability, and contribute to maintain the elderly as well integrated members of society and enable them to enjoy the highest quality of life.